During pregnancy plasma cortisol concentrations are elevated without the compensatory decrease in plasma ACTH concentrations that would be expected with cortisol feedback inhibition of ACTH. The proposed studies examine the control of basal and stress-induced ACTH secretion during pregnancy, in particular the interaction between cortisol and progesterone in control of ACTH, and the role of placental ACTH. The dose-response relation between plasma cortisol and both basal ACTH and ACTH responses to stress will be compared among ovariectomized nonpregnant ewes, ovariectomized nonpregnant ewes infused with progesterone, nonpregnant cycling ewes and pregnant ewes to determine if progesterone alters the dose-response curve between cortisol levels and inhibition of ACTH, and if such an effect accounts for altered cortisol-ACTH relations in pregnancy. ACTH responses to a variety of stimuli, including hypotension, hypoglycemia and corticotropin-releasing factor, will also be compared in nonpregnant, nonpregnant progesterone-infused, and pregnant ewes to determine if progesterone during pregnancy alters ACTH response to stress. The profiles of plasma cortisol, progesterone and ACTH during ovine pregnancy will also be examined to see if changes in plasma progesterone correlate with changes in basal plasma ACTH, total cortisol, and free cortisol concentrations. The contribution of placental ACTH to total ACTH secretion under basal and stimulated conditions will be calculated. Placental ACTH secretion will be calculated using the Fick Principle: femoral arterial and uterine venous ACTH concentrations will be measured, and uterine blood flow will be measured using the radionuclide microsphere techniques. These studies will lead to a better understanding of the normal physiology of the pituitary-adrenal system during pregnancy and may aid in understanding abnormal function in pregnancies complicated by Cushing's syndrome.